Male hypogonadism results from failure of the testes to produce sufficient sex hormones. Aging is the greatest cause of primary hypogonadism, otherwise known as testosterone deficiency syndrome (TDS), and in the United States affects 4-5 million men, while undiagnosed cases of TDS are upwards of 20 million men. TDS adversely affects male health and has been linked to several diseases of aging with large treatment markets including Alzheimer's disease (AD), Type 2 diabetes, cardiovascular disease and osteoporosis. TDS is a major medical challenge; the current monotherapy, of testosterone (T) supplementation, is insufficient to completely reverse hypogonadism, and comes with numerous drawbacks including: 1) dosage issues, 2) inability to replicate dynamic circulating T concentrations, 3) suppression of endogenous T production, 4) testicular shrinkage, and 5) infertility and health risks (cancer, blot clots). TDS is a direct result of the ~1-2% decline per year (starting at age 30) in testicular Leydig and Sertoli cells, those cells that normally produce the testicular hormones T, inhibins, anti-Mllerian hormone and other reproductive hormones. To address this significant medical problem that is poorly addressed by available therapeutic methods, JangoBio has developed a proprietary method that rebalances circulating sex hormones by repopulating the testes with those cells that normally produce sex hormones. This technology comes with numerous advantages including the complete and long-term rebalancing of circulating sex hormones. In this grant, JangoBio will generate safety data and refine our therapy for downstream applications by using the Brown-Norway rat TDS model. Mesenchymal stem cells (MSCs), those cells that normally differentiate into gonadal cells during embryogenesis, will be transplanted into the testes to: 1) examine the safety of stem cell transplantation (assessments of infection, neoplasia, immune rejection, pathology), 2) refine stem cell transplantation (injected cell number; unilateral vs bilateral injection) for optimizatio of rebalancing circulating sex hormones. This will be achieved by examining how the spatiotemporal integration and differentiation of hMSCs into gonadal cell types (assessed by immunohistochemistry & fluorescent in situ hybridization) translates into temporal changes in circulating sex steroids, inhibins and gonadotropins, and 3) the use of this treatment in preventing age-related cognitive decline, examined using a battery of cognitive, behavioral and motor skill tests. This Phase I grant will provide safety data and therapy optimization for the immediate implementation of autologous stem cell treatments in both human (stem cell clinics) and animal (stud farms, veterinary clinics) applications. This safety data also will meet our longer-term goal for obtaining IND approval to commence a Phase I allogeneic stem cell clinical trial for the treatment of hypogonadism. The cognitive data will provide an additional and novel therapeutic avenue for treating cognitive decline. A subsequent Phase II grant would focus on testing this technology in a Phase I clinical trial of TDS or AD.